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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
  • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
  • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

• Myopia or short-sightedness, is a refractive disorder arising from a mismatch between the optical power of the eye and its axial length. This mismatch is a result of excessive elongation of the eye during development and into young adulthood, which leads to the focal plane of distant objects falling in front of the retina, instead on it, causing the image to appear blurred.
• Myopia is now recognized as a leading cause of visual impairment and low vision world-wide (Holden, B. A. et al. 2015). Over the past 50 years, myopia rates have increased dramatically, with some estimates predicting that half of the world’s population could be affected by short-sightedness by 2050. The rapid rise in myopia prevalence is most evident in educationally developed areas of East and Southeast Asia (Morgan, I. G. et al., 2012).
• the increase in the prevalence of myopia pose two main challenges.
• the first challenge is the need to provide optical or other corrections for the associated refractive error for a large percentage of the population.
• the second, and arguably an even greater challenge comes from the increased prevalence of high myopia, and its associated sight-threatening pathological changes (Morgan, I. G. et al., 2017). Correction of refractive error does not prevent the development of these pathological changes, the chances of which increase with the severity of myopia, as it does not address the excessive elongation of the eye.
• Such pathologies include chorio-retinal changes including retinal detachments, myopic macular degeneration, and staphyloma, as well as an increased risk of other sight-threatening conditions such as glaucoma and cataracts (Ohno-Matsui, K., 2017).
• the US National Eye Institute has estimated the annual cost for treating refractive disorders in the US alone at just under $14 billion in 2010 and rising (Rein, D. B., 2013), not including considerable indirect costs such as lost productivity. [0004]
• Myopia and high myopia were estimated to affect 27% (1893 million) and 2.8% (170 million) of the world population, respectively, in 2010.
• MMD myopic macular degeneration
• dopaminergic activity appears to underlie the mechanism by which bright light exposure, or exposure to brief periods of normal vision, prevents the development of experimental myopia, specifically form-deprivation myopia (FDM), in the chick (McCarthy, C. S. et al., 2007).
• FDM form-deprivation myopia
• L-Dopa and some of its metabolites have been shown to have pro-oxidant properties, and oxidative stress has been shown to increase the pathogenesis of Parkinson’s disease (Mao J, et al., 2010).
• Promotion of free-radical formation by L-Dopa seems to directly affect its potential as a treatment for myopia due to the fact that free-radicals could cause further damage to proteins that are responsible for controlling structural proteins in the eye.
• L-Dopa and some of its metabolites such as dopa/dopamine and quinone are toxic for nigral neurons. The toxic effect of L-Dopa limits its use for the treatment of myopia.
• Cataracts are the leading cause of blindness (51%) worldwide according to the World Health Organization (WHO), particularly in low- and middle-income countries. Data dating back to the beginning of this millennium showed that 30-60% of blindness in Africa and 60- 80% in South-East Asia is attributable to cataracts. In the United States, the current number of those with cataract is estimated to be more than 25.7 million. Projections from Prevent Blindness research estimate that the number will increase to 38.5 million by 2032, and to 45.6 million by the year 2050. Cataract is a clouding of the eye’s lens which blocks or changes the passage of light into the eye. Cataracts usually form in both eyes, but not at the same rate.
• WHO World Health Organization
• cataracts can develop slowly or quickly, or progress to a certain point, then not get any worse. Besides aging, other factors may cause cataracts to form. Eye infections, some medicines (such as steroids), smoking, injuries, trauma, or exposure to intense heat or radiation may cause cataracts. Too much exposure to non-visible sunlight (called UV or ultraviolet light) and various diseases, such as diabetes or metabolic disorders, may also contribute to cataracts formation.
• UV or ultraviolet light non-visible sunlight
• Presbyopia is the loss of accommodative ability of the eye resulting in the inability to focus on near objects. Presbyopia affects everyone over the age of 45 and has significant negative impacts on the quality of life.
• Current treatments for presbyopia include: (i) non- invasive approaches that utilize devices to help improve near and distance vision but do nothing to restore the natural process of accommodation and require constant use of the devices, and (ii) invasive surgical procedures which are associated with major complications including decrease in vision quality, regression effects, anisometropia, corneal ectasia, and haze. Most importantly, none of these methods can reverse presbyopia. Moreover, no treatment option exists that can either prevent or delay the onset of presbyopia.
• CM ciliary muscle
• proteins known as crystallins play a major role in the opacification and stiffening of the eye lens.
• the lens crystallins comprise three isoforms, a, P, and y and make up 90% of the eye lens protein content, a crystalline (AC), an ATP- independent chaperone and member of the small heat shock protein (sHsp) family, constitutes 40% of the crystallin protein content. It exists as a hetero-oligomer of two subunits, aA- crystallin (AAC) and aB-crystallin (ABC) and its expression is primarily restricted to the eye lens.
• AAC aA- crystallin
• ABSC small heat shock protein
• presbyopia is the earliest observable symptom of age-related nuclear (ARN) cataract, a major cause of blindness in the world.
• the present disclosure provides an alternate approach, which is to prevent the breakdown of endogenous dopamine by inhibiting the enzymes responsible for its metabolism using safe and effective small molecule inhibitors that can be delivered topically to the retina.
• COMT Catechol-O-methyl transferase
• MAO Monoamine oxidase
• ICso 3OO nm, MW 265.2 Da Nitecapone
• Entacapone IC50 151 nm, MW 305.3 Da
• Tolcapone IC50 773 nm, MW 273.2 Da
• Nebicapone IC50 3.7 nm, MW 273.2 Da
• Opicapone Ki 1 nm, MW 413.2 Da
• BIA 3-335 Ki 6 nm, MW 439.4 Da
• Bifunctional inhibitor IC50 300 nm, MW 346.3 Da.
• IC50 is the concentration of the inhibitor that affords a 50% inhibition in the activity of the enzyme, COMT.
• SMDs small molecule disaggregases
• hAAC human ACC
• SMDs small molecule disaggregases
• Several SMDs were identified based on this approach. It is believed that these SMDs are useful for the treatment and management of presbyopia, and for the treatment and/or slowing down the progression of cataract.
• the cataract can be age-related (nuclear sclerotic, cortical, and posterior subcapsular), congenital, familial, secondary, traumatic, smoke-related and radiation cataracts.
• FIG. 1 depicts synthesis and metabolism of dopamine.
• the enzymes, COMT and MAO are enzymes involved in the metabolism of dopamine.
• FIG. 2 represents data relating to UVC/H2O2-induced aggregation of bovine lens extracts, as described in Example 4.
• FIG. 3 and FIG. 4 represents data relating to Example 5.
• the present disclosure related to compounds useful for the treatment of conditions of the eye, and methods using COMT inhibitors and prodrugs thereof.
• the inhibitors of COMT and prodrugs can be used as standalone (monotherapy) or in combination with inhibitors of monoamine oxidase for the treatment and/or management of conditions of the eye.
• the COMT inhibitors can be used in combination with L-Dopa and/or carbidopa.
• the COMT inhibitors can also be used in combination with atropine.
• the COMT inhibitors can be used in combination with one or more of: L-Dopa, carbidopa, and atropine.
• COMT inhibitors and their prodrugs for the treatment of conditions of the eye. These compounds may be delivered using one or a combination of following approaches: (i) topical; (ii) intravitreal; (iii) systemic; (iv) formulated as a device; (v) nanoparticle; (vi) formulated as gel; (vi) coated on to a device (such as glasses and/or contact lenses).
• Ria and Rib are the same or different, and each of Ri a and Rib is independently selected from the group consisting of: hydrogen, (Ci-C3)alkyl, halo(Ci-C3)alkyl, (C3-Ce)cycloalkyl,
• - R2 is selected from the group consisting of: hydrogen, NO2, and (Ci-Ce)alkyl;
• R3 and R4 are the same or different, and each of R3 and R4 is independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3-Ce)cycloalkyl, and halo(C3-Ce)cycloalkyl; and
• R 6a , R 6b , R 7 are the same or different and are each independently hydrogen or a (Ci- C6)alkyl;
• R 8 is selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl, and
• R 9 is selected from the group consisting of (C1-C6)alkyl, halo(C1-C6)alkyl, (C3- Ce)cycloalkyl, halo(C3-C6)cycloalkyl, aryl, and haloaryl;
• - Rioa and Riob are the same or different, and each of Rioa and Riob is a halogen;
• R11 R12, R13, R14, RI5, R16, R17, R18, R19, R20, R21, R23, R26, and R27 are the same or different, and each is independently selected from the group consisting of hydrogen, branched or linear (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, and halo(C3- C6)cycloalkyl;
• - R22 is CH3 or CF3; - R24 and R25 are the same or different, and each of R24 and R25 is independently selected from the group consisting of hydrogen, (Ci-C3)alkyl, halo(Ci-C3)alkyl, (C3-Ce)cycloalkyl, - Rc, RD, RE, and RF are each the same or different, and each independently are selected from the group consisting of: hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-Ce)cycloalkyl, and hydroxyl;
• Ci -alkyl O, or a direct bond
• - m and z are each independently a number from 0 to 3, or any range of numbers within 0 to 3;
• - n and p are each independently a number from 0 to 10, or any range of numbers within 0 to 10;
• - q is a number from 1 to 10, or any range of numbers within 1 to 10.
• At least one of R 1a and R1b is not hydrogen. In some aspects, at least one of R 1 a and R1b is hydrogen. In some aspects, both R 1a and Rib are not hydrogen. In some aspects, Rib is hydrogen. In some aspects, Ri a and Rib are the same. In some aspects, R 1a and Rib are different.
• R2 is NO2. In some aspects, R2 is NO2, Rib is hydrogen, and R1a is not hydrogen.
• n and p are each independently a number from 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2, or 0 to 1.
• the compound is a compound of Formula (I), wherein: (a) if R5 is then at least one of Ri a , Rib, R24, and R25 is not hydrogen, and
• R 1a and R1b are the same or different, and each of R 1a and Rib is independently selected from the group consisting of: hydrogen, (Ci-C3)alkyl, halo(Ci- C3)alkyl, (C3-C6)cycloalkyl, halo(C3-Ce)cycloalkyl, n some embodiments, R 6a , R 6b , and R 7 are each independently hydrogen, (Ci-Ce)alkyl, a (Ci- Cs)alkyl, (Ci-C4)alkyl, (Ci-C3)alkyl, (Ci-C2)alkyl, or a (Ci)alkyl.
• Ri a and Rib are the same or different, and each of Ri a and Rib is independently selected from the group consisting of: hydrogen, (Ci-C3)alkyl, halo(Ci-
• one of Ri a and Rib is hydrogen, and the other i wherein one or both of Rn and
• R12 is C2H5 or CH3. In some aspects, the one of Rn and R12 is C2H5 or CH3 and the other is hydrogen.
• R14 is C 2 H 5 or CH 3
• R15, Ri6, R17, RIS, R19, R20, R21, R23, R26, and R27 is hydrogen.
• n is a number from 0 to 3.
• R4 R15, Ri6, R17, RIS, R19, R20, R21, R23, R26, and R27 is hydrogen. [0035] In some aspects, R5 and one or more of
• R4, R15, Ri6, R17, RIS, R19, R20, R21, R23, R26, and R27 is hydrogen.
• m is a number from 0 to 3.
• R5 is more of R4,Ri5, Ri6, R17, Ris, R19, R20, R21, R23, R26, and R.2? is hydrogen.
• z is a number from 0 to 5, or 0 to 3.
• X is a direct bond or a Ci -alkyl.
• n and p are each independently 0 or 1.
• R 6a and R 6b are the same.
• RH and Rj are each independently a (Ci-Csjalkyl.
• At least one of Ri a and Rib is and the other is hydrogen. In some aspects, each of Ri a and Rib are independently is
• the compound when one or both of Ri a and Rib is not hydrogen, the compound is obtained by a process comprising reacting a compound wherein both Ri a and Rib are hydrogen to obtain the compound wherein one or both of Ri a and Rib is not hydrogen.
• RAand RB are the same or different, and each of RAand RB is independently selected from
• Rc, RD, RE, and RF are each the same or different, and each independently are selected from the group consisting of hydrogen, branched or linear (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3- Ce)cycloalkyl, halo(C3-Ce)cycloalkyl, and hydroxyl;
• - RG is selected from the group consisting of branched or linear (Ci-Ce)alkyl; halo(Ci-
• Ce)alkyl (C3-C6)cycloalkyl; halo(C3-Ce)cycloalkyl; aryl; haloaryl; and
• RH and Rj are each the same or different, and independently a branched or linear (Ci- Ce)alkyl,
• RK is branched or linear (Ci-Ce)alkyl, aryl, or
• - X is a Ci -alkyl, O, or a direct bond
• - n is a number from 0 to 10, or any range of numbers within 0 to 10;
• - p is a number from 0 to 10, or any range of numbers within 0 to 10;
• - q is a number from 1 to 10, or any range of numbers within 0 to 10;
• n and p are each independently a number from 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2, or 0 to 1.
• the compound is a compound of Formula (II), wherein at least one of RA and RB is not hydrogen. In some aspects, both RA and RB are not hydrogen. In some aspects, RB is hydrogen. In some aspects, RA and RB are the same. In some aspects, RA and RB are different.
• RAand RB are the same or different, and each of RAand RB is independently selected from the group consisting of: hydrogen, [0044]
• X is a direct bond or a Ci-alkyl.
• n and p are each independently 0 or 1.
• RH and Rj are the same.
• RH and Rj are each independently a (Ci-Cslalkyl.
• the compound when one or both of RAand RB is not hydrogen, the compound is obtained by a process comprising reacting a compound wherein both RAand RB are hydrogen, to obtain the compound wherein one or both of RA and RB ib is not hydrogen.
• each of RAand RB are independently i
• the present disclose provides compounds of Formula (Ila), (lib), (lie), (lid), (lie), (Ilf), ar
• the present disclosure provides compounds of Formula (Illa), (IVa), (Va), (Via),
• each of Zi, Z2, Z3, and Z4 is the same or different, and each of Zi, Z2, Z3, and Z4 is independently selected from the group consisting of: hydrogen, (Ci-C3)alkyl, halo(Ci-
• R 6a , R 6b , R 7 are the same or different and are each independently hydrogen or a (Ci-Ce)alkyl;
• R 8 is selected from the group consisting of hydrogen, (Ci-Ce)alkyl, aryl, and
• R 9 is selected from the group consisting of (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3- Ce)cycloalkyl, halo(C3-Ce)cycloalkyl, aryl, and haloaryl;
• Ci -alkyl O, or a direct bond
• - m is a number from 0 to 3;
• - n and p are each independently a number from 0 to 10;
• At least one of Zi and Z2 is not hydrogen. In some aspects, at least one of Zi and Z2 is hydrogen. In some aspects, both Zi and Z2 are not hydrogen. In some aspects, Z2 is hydrogen. In some aspects, Z2 are the same. In some aspects, Zi and Z2 are different.
• Zi and Z2 are each independently selected from the group consisting of
• one of Zi and Z2 is hydrogen and the other is selected from the group consisting of
• n and p are each independently a number from 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2, or 0 to 1 .
• At least one of Zi, Z2, Z3, and Z4 is not hydrogen. In some aspects, at least one Z1, Z2, Z3, and Z4 is hydrogen. In some aspects, one, two, or three of Zi, Z2, Z3, and Z4 is hydrogen. In some aspects, none of Z1, Z 2 ,Z 3 , and Z4 is hydrogen. In some aspects, one, two, three, or four of Zi, Z2, Z3, and Z4 is the same. In some aspects, one, two, three, or four of Zi, Z2, Z3, and Z4 is different.
• the compounds of Formula (Illa), (IVa), (Va), (Via), (Vila), (Villa), or (IXa) or a solvent or salt are obtained by reacting the compounds of Formulas (III), (IV), (V), (VI), (VII), (VIII), or (IX), respectively:
• the compounds of Formulas (III), (IV), (V), (VI), (VII), (VIII), or (IX), can be used as a starting material to prepare the compounds of Formula (Illa), (IVa), (Va), (Via), (Vila), (Villa), or (IXa), respectively.
• the compounds may be obtained as described in any of the following, or obtained using starting compounds described in the following, which are each incorporated by reference in their entirety: Canadian Patent No. 2,342,634; Learmonth et al. Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase. J Med Chem.
• compounds of the present disclosure that are pro-drugs may be made by a process, such as the one shown below, which is a representative scheme.
• the starting materials and reagents used for reacting with the -OH group are merely examples and each may be selected as appropriate based on the desired end product.
• the present disclosure provides the following compounds, or a salt or solvate thereof
• the present disclosure provides pharmaceutical compositions comprising the above compound and a pharmaceutically acceptable excipient.
• the present disclosure also provides methods of using the above compounds, comprising administration to a subject in need thereof.
• the present disclosure provides a pharmaceutical composition comprising any of the compounds, or solvents of salts thereof, in the disclosure, and a pharmaceutically acceptable excipient.
• the pharmaceutical composition comprises a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Illa), (IVa), (Va), (Via), (Vila), (Villa), or (IXa).
• the pharmaceutical composition further comprises one or more additional agents, and the methods discussed herein provide for co-administration of one or more additional agents.
• the additional agent is a compound suitable for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition or disorder associated with the eye, including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia, and any other condition that would benefit from administration of a COMT inhibitor or a compound that has an inhibitory effect on COMT.
• the additional agent is a monoamine oxidase inhibitor (MAOI).
• MAOIs include, but are not limited to: isocarboxazid, selegiline, moclobemide, rasagiline, clorgyline, benmoxin, echinopsidine, mebanazine, metralindole, paragyline, phenelzine, and tranylcyclopramine.
• the COMT inhibitor or compound having an additional effect on COMT, or the additional agent is L- Dopa and/or carbidopa.
• the additional agent is a COMT inhibitor or a further COMT inhibitor or any compound having an inhibitory effect on COMT.
• the additional agent is nitecapone, entacapone, nebicapone, tolcapone, BIA 3-3335 (l-(3,4- Dihydroxy-5 -nitrophenyl)-3 - ⁇ 4- [3 -(trifluoromethyl)phenyl] - 1 -piperazinyl ⁇ - 1 -propanone dihydrochloride), or bifunctional inhibitor compounds such as N,N'-(propane-l,3- diyl)bis(3,4-dihydroxybenzamide).
• the additional agent is atropine.
• the additional agent is a non-steroidal anti-inflammatory agent.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising: a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Illa), (IVa), (Va), (Via), (Vila), (Villa), (IXa); atropine; and one or more pharmaceutically acceptable excipients.
• the additional agent is in pro-drug form or not in pro-drug form.
• the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering any of the compounds, or solvents of salts thereof, in the disclosure, to the subject.
• TTR transthyretin
• the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering any of compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Illa), (IVa), (Va), (Via), (Vila), (Villa), (IXa), or a solvent or salt thereof to the subject.
• a condition selected from the group consisting of presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye
• the present disclosure provides methods of reducing or inhibiting the formation of, or dissolving high molecular weight aggregates of human a-A-crystallin, or to treat, prevent, or reduce the occurrence of or to reduce, ameliorate, or alleviated symptoms associated with conditions relating to human a-A-crystallin and conditions including but not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt- akob, Gerstmann-Straussler- Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, comprising administering an effective amount of any of the compounds of the present disclosure.
• TTR transthyretin
• myopia includes but is not limited to high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM) and lens induced myopia (LIM).
• the compound may be administered as monotherapy or with an additional agent.
• the present disclosure provides methods of administering a compound of the present disclosure and an additional agent, and methods of administrating a pharmaceutical composition comprising a compound of the present disclosure, an additional agent, and one or more pharmaceutically acceptable excipients.
• the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition of the eye, including but not limited to myopia, in a subject in need thereof, comprising administering to the subject any of the compounds of the present disclosure and one or more additional agents, including but not limited to atropine.
• the coadministration with one or more additional agents may provide synergistic effects.
• the co-administration with atropine may provide synergistic effects.
• the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition to a subject in need thereof, comprising administering to the subject a COMT inhibitor or any compound having an inhibitory effect on COMT.
• the condition is a condition of the eye.
• the condition of the eye is myopia, including but not limited to high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM) and lens induced myopia (LIM).
• the condition of the eye is presbyopia, cataract, transthyretin (TTR)- associated amyloidosis.
• the condition is a condition relating to human a-A- crystallin and conditions including but not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome
• TTR transthyretin
• the COMT inhibitor or compound having an inhibitory effect on COMT may or may not be a pro-drug.
• the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition to a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a COMT inhibitor or any compound having an inhibitory effect on COMT, and one or more pharmaceutically acceptable excipients.
• the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition to a subject in need thereof, comprising administering to the subject L-dopa and/or carbidopa, or a pharmaceutical composition comprising L-dopa and/or carbidopa and one of more pharmaceutically acceptable excipients.
• the condition is a condition of the eye, including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia
• the condition is a condition relating to human a-A-crystallin and conditions including but not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt- Jakob, Gerstmann-Straussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome.
• the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition, such as a condition of the eye, including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Hg)> (Hla), (IVa), (Va), (Via), (Vila), (Villa), (IXa); and atropine.
• a condition of the eye including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia in a subject in need thereof, comprising administering to
• the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition of the eye, including but not limited to myopia, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising: a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (IHa), (IVa), (Va), (Via), (Vila), (Villa), (IXa); atropine; and one or more pharmaceutically acceptable excipients.
• the condition is myopia.
• the present disclosure provides methods of administering any of the compounds of the present disclosure and one or more of: atropine, L-Dopa, and carbidopa. In some aspects, the present disclosure provides methods of administering any of the compounds of the present disclosure, atropine, and optionally L-Dopa and/or carbidopa. In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, one or more pharmaceutically acceptable exciepints, and further comprising one or more of: atropine, L-Dopa, and carbidopa.
• the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, atropine, one or more pharmaceutically acceptable excipients, and optionally L-Dopa and/or carbidopa.
• the combination of one or more of atropine, L-Dopa, and/or carbidopa provide a synergistic effect.
• the combination of any of the compounds of the presently claimed invention and one or more of atropine, L-Dopa, and/or carbidopa provide a synergistic effect.
• the combination of a compound of Formula (IVa), (Va), (Via), (Vila), (Villa), (IXa) with one or more of atropine, L-Dopa, and/or carbidopa provide a synergistic effect.
• the compounds of the present disclosure are administered in an amount effective for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye.
• pharmaceutical compositions comprise a compound of the present disclosure in an effective amount.
• the compounds of the present disclosure may be administered through any route of administration, including but not limited to oral, nasal, intranasal, intramuscular, intravenous, subcutaneous, rectal, sublingual, intrathecal, transdermal, intraocularly, inhalation or other topical.
• the compounds of the present disclosure are administrated intraocularly or topically to the eye.
• the pharmaceutical composition is an ophthalmic solution or suspension comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients suitable for administration to the eye.
• the conditions include but are not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt- Jakob, Gerstmann-Straussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasiacleft lip/palate syndrome
• TTR transthyretin
• Methods used to deliver compounds described herein to the eye include, but are not limited to: (i) topical, (ii) (iii) subconjunctival, (iv) intravitreal, (v) systemic, (vi) using a device using a formulation suitable for the device (vii) as nanoparticles (vii) as a gel with suitable formulation, (viii) coated on to a device (such as contact lenses).
• topical administration such administration is typically accomplished using eye drops.
• Contact time on the eye surface is short, but can be prolonged using specific formulations, e.g., gels, gelifying formulations, ointments, and inserts.
• specific formulations e.g., gels, gelifying formulations, ointments, and inserts.
• the basic nature of the solution containing the drug composition is aqueous and as such, agents designed to increase the viscosity of the solution may be employed.
• agents include, for example, hydroxypropyl methylcellulose, carbopol, polyvinyl alcohol, and the like.
• An injectable composition suitable for intraocular injection typically comprises a solution of the drug or a fine particle suspension, which may enable sustained delivery to the eye.
• Formulations are usually aqueous and may commonly include solubilization enhancers such as, but not limited to, polyvinyl alcohol, Tween 80, solutel, cremophore, and cyclodextrin. These solubilization enhancers may be used in combination.
• the formulation is typically in the pH range of 3-8, which is regarded as acceptable for intravitreal formulations. To achieve an acceptable pH, buffering systems are sometimes used. These include but are not limited to citrate and phosphate based buffering systems.
• the tonicity of the intravitreal formulation may be adjusted to remain within a desirable range which typically would be 250-360 mOsm/kg. Adjustment of tonicity may be achieved for example by addition of sodium chloride.
• intravitreal formulations are produced by sterile manufacture for single use. Preserved formulations can be used, for example, formulations containing a preservative such as benzoyl alcohol.
• the dose of the active agent in the compositions of the invention will depend on the nature and degree of the condition, the age and condition of the patient and other factors known to those skilled in the art. Administration can be either as a single injection with no further dosing or multiple injections.
• systemic medication is required for posterior segment therapy and to complement topical therapy for the anterior segment.
• the posterior segment always requires systemic therapy, because most topical medications do not penetrate to the posterior segment Retrobulbar and orbital tissues are treated systemically.
• the present disclosure provides a method of treating conditions of the eye that requires administration of an effective amount of a composition comprising a compound described herein, the compound being present in a prodrug form, or being converted to a prodrug form.
• Prodrug formulations use pharmacologically inactive derivatives of drug molecules that are better able to penetrate the cornea (e.g., they are more li pophilic) than the stand ard formulation of the drug. See review by Brian G. Short, Toxicologic Pathology, 36:49-62, 2008. As described in the review and the references cited therein, within the cornea or after corneal penetration, the prodrug is either chemically or enzymatically metabolized to the active parent compound. Enzyme systems identified in ocular tissues include esterases, ketone reductase, and steroid 6 ⁇ -hydroxylase.
• prodrugs are delivered conventionally by topical application such as antiviral prodrugs ganciclovir and acyclovir, although ganciclovir has also been delivered intravitreally by injection or as a nonbiodegradable reservoir.
• Delivery of a drug with a nonnatural enzyme system in the cornea has been achieved with topical 5-fturocytosine, a prodrug of 5-fluorouracil, administered after subconjunctival transplantation of cells containing the converting enzyme cytosine deaminase.
• Increased corneal penetration into the anterior segments can be achieved with the addition of permeability enhancers to the drug formulation.
• Surfactants, bile acids, chelating agents, and preservatives have all been used.
• Cyclodextrins cylindrical oligonucleotides with a hydrophilic outer surface and a lipophilic inner surface that form complexes with lipophilic drugs, are among the more popular permeability enhancers. They increase chemical stability and bioavailability and decrease local irritation, and they have been used with corticosteroids, choloramphenicol, diclofenac, cyclosporine, and sulfonamide carbonic anhydrase inhibitors.
• the present invention includes small molecule inhibitors that are synthesized as prodrugs such that they have a better ability to permeate the cornea.
• halo and “halogen,” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
• alkyl used alone or as a part of a larger moiety such as e.g., “haloalkyl,” means a saturated monovalent straight or branched, substituted or unsubstituted hydrocarbon radical having, unless otherwise specified, 1-10 carbon atoms and includes, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, see-butyl, isobutyl, tert-butyl, n-pentyl n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
• “Monovalent” means attached to the rest of the molecule at one point.
• cycloalkyl used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic, bicyclic or tricyclic substituted or unsubstituted ring system as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms.
• Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl cycloheptenyl, and cyclooctyl.
• Bicyclic cycloalkyl groups include e.g., cycloalkyl group fused to another cycloalkyl group, such as decalin or a cycloalkyl group fused to an and group (e.g., phenyl) or heteroaryl group, such as tetrahydronaphthalenyl, indanyl, 5, 6, 7, 8- tetrahydroquinoline, and 5,6,7,8-tetrahydroisoquinoline.
• An example of a tricyclic ring system is adamantane.
• the point of attachment for bicyclic cycloalkyl groups can be a tether on the cycloalkyl portion or on the aryl group (e.g., phenyl) or heteroaryl group that results in a stable structure. It will be further understood that when specified, optional substituents on a cyloalkyl may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.
• heterocyclyl means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated substituted or unsubstituted heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
• heterocycle means “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” may be used interchangeably.
• a heterocyclyl ring can he attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxetanyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl.
• a heterocylyl group may be mono- or bi-cyclic.
• bicyclic heterocydyl groups include, e.g., unsaturated or saturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aromatic or heteroaiyl ring, such as for example, chronmnyl, 2,3-dihydrobenzo[b][l,4]dioxioyl, tetrahydronaphthyridioyl, indolinonyl, dihydropyrrolotriazolyl, imidazopynmidinyl, quinolinonyl, dioxaspirodecanyl.
• bicyclic heterocydyl groups can be on the heterocydyl group or aromatic ring that results in a stable structure. It will also he understood that when specified, optional substituents on a heterocydyl group may he present on any substitutable position and, include, e.g., the position at which the heterocydyl is attached.
• heteroaryl used alone or as part of a larger moiety as in “heteroarylalkyl”, “heteroarylalkoxy”, or “heteroarylaminoalkyl”, refers to a 5-10 -membered substituted or unsubstituted aromatic radical containing 1-4 heteroatoms selected from N, O, and S and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazioyl, pyrimidinyl, pyrazinyl, indolizinyl purinyl, naphthyridinyl, and pteridinyl.
• heteroaryl may he used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”.
• heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl rings, where the radical or point of attachment is on the heteroaromatic ring.
• Nonlimiting examples indude indolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinuzolinyl, and quinoxalinyl.
• a heteroaryl group may be mono- or bicyclic.
• optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g,, the position at which the heteroaryl is attached.
• the term ”aryl used done or in conjunction with other terms, refers to a 6-14 membered aromatic ring containing only ring carbon atoms.
• the aryl ring may he monocyclic, bicyclic or tricyclic. Non-limiting examples include phenyl, naphthyl or anthracenyl, and the like. It will also be understood that when specified, optional substituents on an aryl group may be present on any substitutable position.
• the aryl group may be unsubstituted or mono-or di-substituted.
• the terms "subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, eats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
• the subject is a human in need of treatment.
• the compounds of the present disclosure may be present in the form of pharmaceutically acceptable salts.
• the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.”
• a compound also includes any tautomer which may be formed. Unless otherwise indicated, reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.
• a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
• a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
• a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
• Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/ cationic salts.
• Pharmaceutically acceptable basic/ cationic sate include, the sodium, potassium, calcium, magnesium, diethanolamine, romethyl-D- glneamlne, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
• Pharmaceutically acceptable acidic/anionic salts include, e.g., the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.
• a prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by the removal of a biologically labile group.
• Prodrug preparation is well known in the art.
• Tautomers are isomers that are in rapid equilibrium with one another.
• tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.
• Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
• alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
• Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
• Example 1 Inhibition of Catechol-O-methyl transferase (COMT)
• 1 pL of an appropriate dilution of the compound is plated into assay wells (black 96-well, round-bottom, polystyrene plates from Corning Inc., Corning, NY, Costar#3792).
• Recombinant enzyme is diluted in Assay Buffer (100 mM Na 2 HPO 4 pH 7.4, 1 mM DTT, 0.005% Tween-20), and 35 pL of the diluted enzyme is added to the assay wells containing 1 pL of the diluted compound.
• the final amount of enzyme in the assay is varied between 1 and 6 ng depending on the preparation of COMT utilized. COMT and the compound are preincubated for about 2 h at room temperature.
• Enzyme reactions are initiated by the addition of 5pL of an 8X mix prepared in Assay Buffer containing 8pM S-adenosyl methionine (SAM) (USB Corporation, Cleveland, OH,#US10601), 16pM dopamine (Sigma-Aldrich, St. Louis, MO,#H8502), and 40 mM MgCb. After a 25 min incubation at room temperature, reactions are quenched with 5 pL of 250 mM EDTA, pH 8.2.
• SAM S-adenosyl methionine
• SAH antibody/SAC TAMRA tracer complex discussed above was pre-formed at room temperature for 30 min while protected from light.
• Example 2 General scheme for making prodrugs
• starting compound 1 and the reagent used for reacting with the OH group are mere examples, and each may be selected as appropriate based on the desired end product.
• n is a number from 1 to 10.
• Example 3 Evaluation the Efficacy of CAP4196 in Myopia Chick Model
• the Myopia chick model developed more than 35 years ago, is one of the major models for Myopia today.
• Major advantages of this model include: (1) relatively large eyes (8 to 14 mm), (2) rapid eye growth of about 100 pm per day, (3) highly sensitive control of refractive state by retinal image quality and focus, (4) excellent optics (diffraction-limited at 2.0mm pupils), (5) Active accommodation (about 17 D), (6) high visual acuity (7 cycles/degree), (7) easy drug delivery by intravitreal injection, (8) Friendly and co-operative nature, and (9) inexpensive and easy to keep
• the amount of the compound injected and the vehicle are as shown below.
• Vehicle for quinpirole Saline (20 pl, 0.75% NaCl w/v) (vehicle for quinpirole) Vehicle for L-DOPA and CAP4196: 0.1% w/v ascorbic acid in 1 * phosphate- buffered saline.(PBS)
• Form deprivation myopia is induced in the right eyes of 4-5 days old chicks by the application of translucent occluders.
• Chicks receive intravitreal injections of the compound or vehicle in the form deprived eye (20 pl/ eye) daily for a total of five days.
• Normal normal
• n 13
• chicks are sacrificed, their sclera labelled in organ culture with 35 SO4, and scleral proteoglycan synthesis measured by CPC-precipitation of newly synthesized glycosaminoglycans.
• Radioactivity is measured using scintillation counting, and the amount of radioactivity is compared (as CPM) between right and left eyes of all groups of animals by paired t-tests and between different groups using ANOVA. Animals are raised in the Oklahoma University Health Science Center (OUHSC) Animal facility.
• OHSC Oklahoma University Health Science Center
• Example 4 Prevention of UVC/H2O2-induced aggregation of bovine lens extracts by CAP1160
• CAP 1160 prevents UVC/H2O2- induced aggregation of bovine lens extracts.
• the structure of CAP1160 is:
• CAP4719 has the following structure:
• PBS phosphate-buffered saline
• chicks are sacrificed, their sclera labelled in organ culture with 35SO4, and scleral proteoglycan synthesis measured by CPC-precipitation of newly synthesized glycosaminoglycans.
• Radioactivity is measured using scintillation counting, and the amount of radioactivity compared (as CPM) between right and left eyes of all groups of animals by paired t-tests and between different groups using ANOVA. Animals are raised in an approved Animal facility and all experimental procedures will be carried out under an institutionally approved IACUC protocol.
• tissue is used for further evaluation using analytical methods to quantify levels of dopamine, metabolites (HVA & DOPAC) and CAP4719 by liquid chromatography mass spectrometry (LC/MS).
• the right eyes were goggled (myopic) and injected with either the high dose, low dose, or vehicle of the CAP4719 compound.
• Proteoglycan synthesis was measured as the amount of 35SO4 (cpm) incorporated into glycosaminoglycans four hours after the final dose. It is expected that the right eye has a higher rate of proteoglycan synthesis.
• the higher rate of proteoglycan synthesis is related to the increased growth rate of the myopic eye.
• Application of the high and low doses of the compound did not completely block the increase in proteoglycan synthesis, but the percentage increase over the left (control) eye appears to be lower in the CAP4719 treated eyes compared with the vehicle.
• the lower rate of proteoglycan synthesis in the right eyes of the treated eyes would be expected to cause a slower rate of elongation (and less myopia) compared with the vehicle treated eyes. Results are shown in FIG. 3 and FIG. 4.

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